The present invention relates to the synthesis of anthracycline compounds and particularly compounds such as daunomycinone which are constituents of anti-cancer antibiotics such as doxorubicin and daunorubicin.
Anthracycline antibiotics have been found effective in treating a wide variety of cancers including acute myeloblastic and lymphoblastic leukemia and as a result their synthesis has attracted considerable attention. These antibiotics occur as glycosides formed of a tetracyclic aglycone (anthracyclinone) and a 3-amino-2,3,6 trideoxy sugar and can be represented by the formula (I): ##STR1## In this formula use of the following constituent groups leads to the compounds as listed:
______________________________________ R = H R' = OCH.sub.3 Daunorubicin R = OH R' = OCH.sub.3 Doxorubicin R = OH R' = OH Carminomycin ______________________________________
The antibiotic doxorubicin is the subject of U.S. Pat. No. 3,590,028 and is available as the hydrochloride under the label "Adriamycin".TM. from Adria Laboratories, Inc., Dublin, Ohio. Adriamycin has been used successfully to produce regression in several carcinoma and disseminated neoplastic conditions and is a prescribed antineoplast.
Conventionally, anthracycline antibiotics are produced by aerobic fermentation of strains of Streptomyces. However, fermentations are inherently restricted in terms of the amounts of antibiotic they yield, the nature of the antibiotics produced and the conditions and apparatus under which they can be successfully conducted. Fermentations are also incapable of yielding analogues. Thus there is a need for more versatile synthesis of these compounds. More particularly there is a need for syntheses able to yield derivatives of these compounds which may be more effective than the natural substances. Accordingly, efforts have been directed to developing effective and flexible synthetic routes to these tetracycline type antibiotics.
One synthesis which has been treated somewhat extensively in the literature provides the antibiotics in good yields by coupling the separately prepared aglycone and amino sugar. Under this approach daunorubicin and doxorubicin have been prepared by glycosidation of daunomycinone and adriamycinone, respectively, with daunosamine derivatives. Using this process the major constituents of the antibiotics are separately synthesized and it is possible to individually modify the structure of the aglycone and amino sugar and thereby obtain access to a variety of antibiotic derivatives. The present invention has for its object synthesis of the anthracyclinone moiety of these antibiotics.
While the aglycones constituting these antibiotics have been artificially synthesized before, the synthetic routes used have not been satisfactory. They have been particularly unsuitable for manufacturing the asymmetric aglycones such as daunomycinone because it has only been possible to obtain the regioselectivity that is required by adding numerous steps to the synthesis.
Alexander and Mitscher, Tetrahedron Letters, 3043 (1978), disclose a convenient synthesis of symmetrical anthracyclines from a decalin embodying major elements of two rings of the final antibiotic and coupled this through an organometallic reagent with a phthalic ester to provide the remaining rings of the quinone system. This product was further elaborated by well-established means. The reaction is shown in Equation I below and it will be noted that it is similar to the present invention in that the synthesis relies upon a bromination and subsequent conjugation of the bromide with a phthalic ester. ##STR2## The principal utility of this synthesis is limited to preparation of analogues symmetrical about the D-ring, because the bromination of the decalin is not specific. Only when used to synthesize symmetric products does the use of a mixture of bromide regioisomers not affect the yield.
Braun, Tetrahedron Letters, 21, 3871 (1980), addresses the regioselectivity problem by using an aliphatic moiety to direct bromination. [Braun is mentioned because it is another approach to regioselectivity. Its inclusion here is not intended as an admission of prior art.] The synthesis proceeds via formation of a 7-bromo,5,8-dimethoxy-.alpha.-tetralone which conjugates with phthalic anhydride yielding a product ultimately used in a ring closure via an organometallic reagent. The synthesis is outlined in Equation II. ##STR3##
Swenton et al, J. Am. Chem. Soc., 100, 6188 (1978) have devised a regiospecific method for synthesizing 7,9-dideoxydaunomycinone in which the key steps involve bromination of 2-hydroxy-5-methoxybenzaldehyde which is further elaborated and then condensed with dimethyl 3-methoxyphthalate to achieve a regiospecific bond formation as shown in Equation III below: ##STR4##
In a much longer sequence, Parker and Kallmerten, J. Am. Chem. Soc. 102, 5881 (1980), synthesized 7,9-dideoxydaunomycinone. The final product is a 7,9,didesoxyanthracycline. The synthesis proceeds via a cyano decalin and the key step is the conjugate addition shown in Equation IV below: ##STR5## Kende, Tetrahedron Letters, 1201 (1979) has developed a similar synthesis, and as with most of these processes regioselectivity is obtained only by adding numerous steps to the process.
The above processes are generally unsuitable for synthesizing the asymmetric anthracycline compounds because regioselectivity is only achieved at the expense of adding numerous steps to the reaction sequence. This limits flexibility in producing analogues and increases the economic investment in each intermediate. They are also not suitable for large scale operations. Accordingly, there is a need for an anthracycline synthesis involving fewer steps, which is amenable to the production of analogues and which can be carried out effectively on a large scale. There is also a need for a synthesis which is able to yield anthracycline derivatives such as daunomycinone which are assymetric about the D-ring.